The “sustained-release fine particles” of the present invention means fine particles that contain a drug, have been submitted to various types of sustained-release treatments, and have a mean particle diameter of approximately 0.1 μm to approximately 350 μm. The various types of sustained-release treatments means treatment to give the quality of “sustained release” that is well known pharmaceutically. Treatment that has given gradual drug releasability, treatment that has given gastrosolubility, treatment that has given enterosolubility, treatment that has given timed releasability, treatment that has given releasability that is a combination of these, and the like, can be given as examples. Moreover, those that have been given enterosolubility are called “enteric sustained-release fine particles.”
Various types of disintegrating tablets in buccal cavity were previously developed so that they could be easily taken, even without water, by persons with weak swallowing ability, including the elderly, children, and the like. Moreover, the demand for the use of an assortment of drugs in recent years has led to the need for providing the function of sustained releasability to quick-disintegrating tablets in the buccal cavity.
First-generation quick-disintegrating tablets in the buccal cavity, for instance, “Zydis™” marketed by R. P. Scherer, and the like, are known to be pharmaceutical preparations manufactured by lyophilization. These first-generation quick-disintegrating tablets in the buccal cavity are basically manufactured by lyophilization, or special drying, using a solution or suspension of the drug. Thus, the process of manufacture in a liquid state was essential, and there was no discussion of providing the function of sustained releasability.
Various second-generation quick-disintegrating tablets in the buccal cavity are known, including those that use the function of disintegrants (Japanese Kokai Patent No. Hei 10-182436, International Early Disclosure Pamphlet WO98/02185, and the like), those characterized in that a saccharide of high moldability is spray coated and/or granulated as binder on a saccharide of low moldability and which can be humidified and dried when tablet strength is further necessary (International Early Disclosure Pamphlet WO 95/20380 (corresponding U.S. Pat. No. 5,576,014, Japanese Patent No. 312141), and the like, and these are manufactured by tableting. Consideration has been given to quick-disintegrating tablets in the buccal cavity containing fine particles that have been sustained-release treated, for instance, coated by a polymer, in order to solve the apparent contradictory problem of providing the function of sustained releasability to these second-generation quick-disintegrating tablets in the buccal cavity. However, even though attempts have been made to simply mix fine particles that have been sustained-release treated with a filler for quick-disintegrating tablets in the buccal cavity and tablet this mixture, segregation occurs due to a difference in apparent specific gravity and a difference in fluidity between the filler and the sustained-release fine particles during the tableting process. The term “segregation” used here is the state where the sustained-release fine particles are not uniformly dispersed in the filler and segregation occurs when they are not uniformly dispersed. It is possible to confirm segregation by determining uniformity of content of drugs that comprise tablets once tablets have been made. For instance, it can be said that if the coefficient of variation (CV %) of the amount of drug, which is shown below, is 0 to 3.5%, segregation will not occur and if the coefficient of variation exceeds 3.5%, segregation will occur. Various problems are produced with this segregation as the cause. For instance, there are the problems of (1) tableting pressure being propagated directly to the sustained-release fine particles due to contact between the punch face and the sustained-release fine particles during tableting, or direct contact between sustained-release fine particles themselves, resulting in destruction of the sustained-release fine particles and acceleration of dissolution after they have been made into tablets, (2) the degree of destruction of the sustained-release fine particles varying with the degree of segregation and therefore, controlled dissolution, which is the design goal of sustained-release fine particle preparation, not being realized with good reproducibility after tablets are made, (3) there being fluctuations in the number of sustained-release fine particles contained in one tablet and it being impossible to guarantee uniformity of drug content, and the like.
An invention relating to a method of manufacturing spherical fine particles that are useful for manufacturing controlled-release pharmaceutical preparations that are easy to take by a special tumbling granulation method is disclosed in International Early Disclosure Pamphlet WO00/24379. This pamphlet gives a manufacturing method involving special tumbling granulation of these spherical fine particles and shows that dissolution is controlled by coating spherical fine particles and that these spherical fine particles can be used in quick-disintegrating tablets in the buccal cavity. However, our research has confirmed that the above-mentioned various problems occur and the purpose cannot be accomplished if quick-disintegrating tables in the buccal cavity simply contain spherical fine particles that have been sustained-release treated. Moreover, there is no disclosure or indication of specific means for dealing successfully with these problems in said specification.
Thus, although as yet unknown, there is a demand for introduction of quick-disintegrating tablets in the buccal cavity comprising sustained-release fine particles with which acceleration of the drug dissolution after being made into a tablet that is the result of destruction of sustained-release fine particles under tableting pressure when tablets are made is inhibited, and controlled dissolution, which is the design goal of sustained-release fine particle preparation, is realized with good reproducibility even after tablets are made, and with which uniformity of drug content is guaranteed.